Antibody-mediated Activation of the FGFR1/Klothoβ Complex Corrects Metabolic Dysfunction and Alters Food Preference in Obese Humans

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2020 Nov 3

PMID 33139537

Citations 46

Authors

Amos Baruch

Chin Wong

Leslie W Chinn

Anjali Vaze

Junichiro Sonoda

Thomas Gelzleichter

Shan Chen

Nicholas Lewin-Koh

Linda Morrow

Suresh Dheerendra

Richard Boismenu

Johnny Gutierrez

Eric Wakshull

Maria E Wilson

Puneet S Arora

Affiliations

Soon will be listed here.

Abstract

Fibroblast growth factor 21 (FGF21) controls metabolic organ homeostasis and eating/drinking behavior via FGF receptor 1/Klothoβ (FGFR1/KLB) complexes expressed in adipocytes, pancreatic acinar cells, and the nervous system in mice. Chronic administration of recombinant FGF21 or engineered variants improves metabolic health in rodents, nonhuman primates, and humans; however, the rapid turnover of these molecules limits therapeutic utility. Here we show that the bispecific anti-FGFR1/KLB agonist antibody BFKB8488A induced marked weight loss in obese cynomolgus monkeys while elevating serum adiponectin and the adipose expression of FGFR1 target genes, demonstrating its action as an FGF21 mimetic. In a randomized, placebo-controlled, single ascending-dose study in overweight/obese human participants, subcutaneous BFKB8488A injection caused transient body weight reduction, sustained improvement in cardiometabolic parameters, and a trend toward reduction in preference for sweet taste and carbohydrate intake. These data suggest that specific activation of the FGFR1/KLB complex in humans can be used as therapy for obesity-related metabolic defects.

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